NHLBI Working Group
Imaging in Peripheral Arterial Disease (PAD)

Executive Summary

The National Heart, Lung and Blood Institute convened a Working Group (WG) of investigators on September 11, 2009 in Bethesda, MD to assess the state of the art of imaging for lower extremity, atherosclerotic PAD. Their charge was to evaluate existing and emerging imaging modalities for PAD by identifying advantages and limitations of each, including impacts on clinical decision-making and patient outcomes. From this framework, the group was asked to provide recommendations to the NHLBI for research goals to advance the field.

Discussion

A clinical overview highlighted the seriousness of PAD in terms of excess risk for cardiovascular morbidity and death, even in the vast majority of individuals who do not develop critical limb ischemia.  Well chosen application of imaging could potentially modify the clinical trajectory of PAD for the better across the full spectrum of disease. Discussion first centered on imaging modalities that are now in different stages of adaptation for use in PAD such as catheter-based angiography (the current gold standard), duplex and contrast-enhanced ultrasound (US), computed tomography angiography (CTA), magnetic resonance angiography (MRA), non-contrast MR, NMR spectroscopy, and molecular imaging by positron emission tomography (PET) or CT. Themes that emerged included:

• Our limited knowledge of the pathophysiology of PAD, particularly in comparison with atherosclerosis of the coronary arteries. In part, this reflects the limited mechanistic insights that can be gained from standard diagnostic tests for PAD such as ankle-brachial index (ABI) and contrast angiography.
• Our inability to extrapolate hard clinical outcomes such as survival from the functional endpoints (e.g., walking distance, time to claudication, and quality of life) often used in clinical trials of PAD.
• The exciting potential for additional imaging techniques to complement the 2-D lumenograms of conventional, catheter-based angiography. Newer methods can supply information, often in three dimensions, about vascular anatomy, blood flow rates, vascular wall architecture and remodeling, muscle perfusion, plaque volume and composition, calcification, intraluminal thrombus, stent positioning and malfunction, vasa vasorum, and soft tissue structure adjacent to vasculature. Furthermore, the noninvasive nature of some modalities lessens risk and allows for serial testing over time.

To identify important goals for future research, discussion turned to how to optimize imaging approaches in various clinical scenarios including the asymptomatic patient with an incidental diagnosis of PAD, the claudicant, the diabetic with foot ulcer, the patient with coincident chronic kidney disease, and the post-interventional patient.

Recommendations

The WG recommended support of the following research goals:

• Develop capability to measure perfusion at rest, and perfusion reserve, particularly in the foot.
• Gain understanding of the natural and treated course of disease in well defined subpopulations of individuals with PAD by incorporating noninvasive imaging tests into large, population-based, (Framingham-like) observational studies.
• Improve understanding of benefits (and risks) from standard and experimental therapies by integrating novel imaging tests into clinical interventional studies of PAD.
• For instance, use molecular imaging to assess inflammation in longitudinal studies of plaque characteristics in patients receiving statins.
• Develop imaging methods to evaluate collateral- and micro-circulations and quantify their respective contributions to clinical outcomes.
• Using imaging and other tools, explore the apparent uncoupling of perfusion and energetics in skeletal muscle in the setting of PAD.
• Develop predictive, imaging-based surrogate endpoints for clinical research in PAD.
• Advance and refine imaging technologies by:
• eliminating or minimizing intravenous contrast and radiation exposure;
• developing and validating novel, less toxic contrast agents;
• identifying novel molecular targets for imaging that will help detect subclinical disease and/or elucidate disease mechanisms;
• tailoring instrumentation for PAD, such as developing advanced receiver coilsfor MRI of the lower leg;
• standardizing requirements for imaging protocols;
• developing a lexicon and standardizing reporting of test results; and
• developing and automating post-processing data analysis methods for applications in PAD.
• Stimulate clinical effectiveness research to determine the better imaging modality or imaging protocol for specific clinical situations. For example, 1) treadmill testing with measurement of ABIs versus 31P energetics for assessing baseline limitations of intermittent calf claudication; 2) contrast-enhanced US versus contrast-enhanced MR for post-exercise muscle perfusion in claudicants.

Publication Plans

A manuscript of the proceedings in a peer-reviewed journal is planned in 2010.

Working Group Members

Chair

• Christopher M. Kramer, M.D., University of Virginia
  

Members

• Zahi A. Fayad, Ph.D., Mount Sinai School of Medicine, New York University
• Bob S. Hu, M.D., Palo Alto Medical Foundation
• Michael R. Jaff, D.O., Massachusetts General Hospital, Harvard University
• Debiao Li, Ph.D., Northwestern University
• Jonathan R. Lindner, M.D., Oregon Health & Science University
• Alan H. Matsumoto, M.D., University of Virginia
• Joel D. Morrisett, Ph.D., Baylor College of Medicine
• Dwight G. Nishimura, Ph.D., Stanford University
• Martin R. Prince, M.D., Ph.D., Cornell and Columbia Universities
• Sanjay Rajagopalan, M.D., The Ohio State University
• Anne Roberts, M.D., University of California, San Diego
• Chun Yuan, Ph.D., University of Washington

Participating Divisions

Division of Cardiovascular Sciences

Last Updated: February 2010